Conveyance of Cortical Pacing for Parkinsonian Tremor-Like Hyperkinetic Behavior by Subthalamic Dysrhythmia

Parkinson’s disease is characterized by both hypo- and hyperkinetic symptoms. While increase of subthalamic burst discharges has a direct causal relation with the hypokinetic manifestations (e.g. rigidity and bradykinesia), the origin of the hyperkinetic symptoms (e.g. resting tremor and propulsive gait) has remained obscure. Neuronal burst discharges are presumed autonomous or reluctant to respond to synaptic input, thereby interrupting the information flow. We, however, demonstrate that generation of subthalamic burst discharges need cortical glutamatergic synaptic input, which is enhanced by A-type K+ channel inhibition. The excessive top-down triggered subthalamic burst discharges can then bottom-up drive highly correlative activities in the motor cortices and skeletal muscles, leading to hyperkinetic behaviors (e.g. tremors) which are readily ameliorated by inhibition of cortico-subthalamic AMPAergic synaptic transmission. We conclude that subthalamic burst discharges could also have a role in information relay, and critically contribute to the pathogenesis of both hypokinetic and hyperkinetic parkinsonian symptoms.